Treatment of Hepatitis B
Geoffrey L. Braden, MD
B remains a major worldwide public health problem. Globally,
there are 350 million carriers of the hepatitis B virus (HBV)
vs 370 million carriers of the hepatitis C virus (Hepatitis C Virus). In the
United States, 4.0 million persons are positive for Hepatitis C Virus
antibodies and 2.7 million of these individuals are chronic
carriers, with positive Hepatitis C Virus polymerase chain reaction (PCR)
In comparison, it is estimated that 1.25 million carriers of
hepatitis B are present in the United States. Although
hepatitis C may be associated with a higher incidence of
chronic hepatitis compared with hepatitis B, and may lead to
cirrhosis in 20% to 25% of patients, chronic hepatitis B leads
to chronic hepatitis and cirrhosis in 15% to 20% of carriers,
and is associated with an even higher incidence of
hepatocellular carcinoma (HCC) in asymptomatic carriers than
is hepatitis C.
The hepatitis B virus is carcinogenic in chronic carriers
without objective evidence of liver disease. The yearly risk
of HCC in asymptomatic hepatitis B carriers is 0.47%. The
incidence of HCC in hepatitis B-related cirrhosis is 2% to 6%
per year, similar to the incidence of HCC in Hepatitis C Virus-related and
other forms of cirrhosis. This tendency for the HBV to induce
hepatic carcinogenesis accounts for the fact that HCC is one
of the leading forms of cancer in China and Southeast Asia.
Asymptomatic carriers of HBV should be screened yearly, using
serum alpha feto-protein studies and liver ultrasound to look
for HCC. Although definitive studies are lacking, HBV patients
with cirrhosis should be screened every 6 months with a serum
alpha feto-protein test and an ultrasound of the liver. This
screening protocol affords the best opportunity to diagnose
small HCCs that can be treated for cure with either a
segmental hepatic resection of the involved area or with liver
transplantation. Currently, liver transplantation is reserved
for patients with HCC who have 3 tumors, all < 3.0 cm in
size, or a single tumor </= 5 cm in size. Palliative
treatment may also be improved with earlier diagnosis of HCC,
although again, screening has not been shown to decrease
mortality in series of patients with HBV and other chronic
This year's Digestive Disease Week meeting provided several
excellent sessions to refine our knowledge of the diagnosis
and treatment of hepatitis B. Robert Perrillo, MD, presented
an American Association for the Study of Liver Diseases (AASLD)-sponsored
state-of-the-art lecture on the treatment of hepatitis B. An
AASLD topic forum on hepatitis B was presented on May 19, and
an AASLD poster session on hepatitis B was held on May 21.
Jenny Heathcote, MD, and K. Rajender Reddy, MD, also
contributed their expertise during luncheon breakout sessions.
This review addresses the natural history of chronic
hepatitis B and the clinical subtypes of carriers of hepatitis
B, and discusses the emerging importance of genotyping in
defining subclasses of patients, including those at risk for
precore/core promoter variants and HCC. The treatment of
hepatitis B with interferon, lamivudine, and other nucleoside
analogues used alone and in combination is also addressed, as
is the use of lamivudine in patients with decompensated
cirrhosis. Finally, the treatment of patients with hepatitis B
e antigen (HBeAg)-negative chronic hepatitis (precore/core
promoter variants) is discussed.
Subtypes of Hepatitis B Carriers
Hepatitis B Surface Antigen (HBsAg)-Positive Adult
form of HBV is the most common subtype found in the United
States. Infection occurs via blood transfusions (mostly before
1976), intravenous-drug use, sexual transmission, and via
horizontal transmission from living with a carrier of
hepatitis B (3%-6% risk). HIV-positive patients who are on
hemodialysis are also at risk. Patients are usually HBeAg-negative
and anti-HBe-positive when the diagnosis is made. These
patients usually have normal liver enzyme levels and quiescent
inflammation on liver biopsy. Once HBeAg seroconversion takes
place, the virus shifts from a replicative stage to an
integrated form, and whatever degree of chronic hepatitis that
was present becomes inactive. HBV DNA is usually negative by
hybridization assays, which is the preferable study for the
evaluation and management of patients with chronic hepatitis
B. The branched DNA assay (Bayer), hybrid capture assay (Digene),
and liquid hybridization assay (Abbott) are sensitive down to
A negative HBV DNA on hybridization assay defines the inactive
carrier state. All of these patients will be positive for HBV
DNA when more sensitive PCR assays such as the Amplicor assay
(Roche) are used. Some of these assays are positive down to
100-400 copies/mL. Generally, patients with < 1,000,000
copies/mL of HBV virus do not have active liver disease. The
latter represents a distinct difference from our management of
viral loads and the standard use of the PCR assay in patients
with chronic hepatitis C. The exception to this rule is the
management of HBeAg-negative chronic hepatitis, which will be
followed 296 asymptomatic HBsAg-positive blood donors from
France for 30 years. Thirty-two percent of these patients
spontaneously lost HBsAg over that time period. Most of the
patients had normal liver enzymes, and a control group was
followed. The hepatitis B carriers had the same overall and
liver-related mortality as the control group.
Neonatal Hepatitis B
hepatitis B is an endemic infection in Southeast Asia and the
South Pacific. Fifty percent or more of HBV infection is
spread by perinatal transmission.
Patients remain immunotolerant of the virus as neonates and
through early childhood. Longstanding persistence of HBeAg is
present and seroconversion occurs later in adulthood. Many of
these patients have high HBV DNA levels as infants but achieve
normal liver function tests as children. These patients often
develop HBeAg-positive chronic hepatitis B with elevated liver
enzymes in adulthood. These patients are an important
reservoir for those who go on to subsequently develop
cirrhosis and HCC. The majority of these patients will
spontaneously seroconvert as adults to the HBeAg-negative,
anti-HBe-positive state. Even though this transition occurs,
considerable liver injury may have already taken place.
Recently, I observed an Asian American patient who had
contracted neonatal hepatitis B from his mother who herself
had emigrated to the United States from Taiwan. He is in his
late 20s, has normal liver enzymes, is HBsAg-positive, HBeAg-negative,
and anti-HBe-positive. His HBV DNA assays are negative by
hybridization, but he has established cirrhosis on liver
biopsy (Geoffrey L. Braden, MD, 2002; personal observation).
In this case, the damage was caused by chronic hepatitis B
infection years before this patient presented to me. As more
individuals with chronic hepatitis B emigrate from Southeast
Asia to the United States, this type of problem is likely to
become more prevalent.
HBV Infection in Patients From Sub-Saharan Africa, Alaska,
and the Mediterranean
these countries, hepatitis B is usually transmitted
horizontally from person to person during childhood. Perinatal
transmission is less common. Most of these children have
elevated alanine aminotransferase (ALT) levels. HBeAg
seroconversion occurs around puberty.
Hepatitis B e Antigen-Negative Chronic Hepatitis B
patients have precore and core promoter mutations and
represent an emerging group of patients with chronic hepatitis
B who have active liver disease. Precore variants involve a
G1896A mutation and core promoter variants involve A1762T and
G1764A mutations in HBV DNA polymerase. These variants arrest
the production of HBeAg during viral replication. These
patients are HBsAg-positive, HBeAg-negative, and anti-HBe-positive.
They have elevated liver enzymes, chronic liver disease, and
relatively low levels of circulating HBV DNA. Although
hybridization assays for HBV DNA are usually positive in this
subgroup, a PCR assay may occasionally be necessary to
quantify the amount of virus that is present. These patients
represent a subgroup that is relatively resistant to treatment
with interferon or lamivudine. It is also important to
remember that although HBeAg synthesis does not occur, the
majority of these patients are anti-HBe-positive. This
subgroup is differentiated from the inactive carrier who has a
similar serologic profile by the fact that elevated
aminotransferases (> 2x normal) are present, along with
active liver disease on liver biopsy. Commercial assays for
these mutations are available to help define this subset. The
prevalence of these mutations ranges from 20% to 90% among
patients originating from Europe and the Mediterranean, 10% to
38% among those from Asia and the South Pacific, and is
approximately 10% among those in the United States.
Use of Genotyping in Hepatitis B
use of genotyping will increase in the future in order to help
define different subtypes of patients. The precore mutation is
more common with genotype D, which is more prevalent in the
Mediterranean, and is rare in patients with genotype A, which
is the most common genotype in the Unites States and Western
Chu and colleagues
looked at the distribution of genotypes in the US population;
all 7 known HBV genotypes were found in this country. The
majority of Americans were found to have genotypes A and C
(67% combined), but there are regional and ethnic differences
in the nationwide breakdown. The precore variant was also
found to be more prevalent in genotype D patients. The core
promoter variant was more common in genotypes C and D.
Genotype D patients showed a higher incidence for developing
Chien and colleagues
looked at variables that affected a sustained response (HBeAg
seroconversion) to lamivudine therapy in a group of Taiwanese
patients. Using a stepwise regression model that examined many
clinical variables, only genotype was found to be the
predictor of a sustained response to lamivudine. Sixty-one
percent and 14% of patients with genotypes B and C,
respectively, had a sustained response. In a related paper,
Watanabe and associates
looked at the association between genotype and the development
of HCC in a group of 100 patients followed for 11 years.
Seventy-four percent of their patients were genotype C and 26%
were genotype B; HCC developed in 25 patients. Genotype C,
along with age, lower platelet counts, and higher gamma-glutamyltranspeptidase
(GGTP) levels were associated with a greater risk of HCC.
Although the number of patients followed in this study was
small, it is possible that genotyping will be used routinely
in the future in the setting of hepatitis B to help define
subgroups of patients at risk for the development of HCC who
will respond to treatment. In contrast to hepatitis C, at
present, there are no reliable data on the response of HBV to
interferon or lamivudine therapy based on genotype.
Treatment of Chronic Hepatitis B
goals of treatment are to decrease or eliminate viral
replication and improve histology, by decreasing the amount of
inflammation present, and either stabilizing or reversing
fibrosis. Other goals are to prevent the development of HCC
and to prolong life.
the early 1990s, interferon was approved for the treatment of
hepatitis B in the United States. The standard dose is 5
million units daily or 10 million units 3 times per week given
subcutaneously for a total of 16 weeks. Patients treated
should have aminotransferase levels that are > 2x elevated,
be HBeAg-positive, and have chronic hepatitis on liver biopsy.
The United States Food and Drug Administration (FDA) has
approved the use of interferon in patients with serum
aminotransferases > 5x normal, but the consensus is that
patients with aminotransferases > 2x normal should be
evaluated for treatment because they have a significant
incidence of chronic hepatitis on liver biopsy and also a
significant likelihood of responding to treatment.
A treatment response is defined as normalization of liver
enzymes, loss of HBV DNA by hybridization assay, and loss of
HBeAg with or without conversion to anti-HBe positivity. A
sustained viral response is defined as maintaining this
improvement for 6 months beyond the end of treatment. Forty
percent of patients with aminotransferases between 100 and 200
U/L and 50% with aminotransferases > 200 will normalize
serum ALT on treatment. Sixty-seven percent of patients with
aminotransferases between 100 and 200 U/L and close to 100% of
those with aminotransferases > 200 will develop
undetectable HBV DNA on treatment.
Thirty-seven percent of patients will develop a sustained loss
of HBV DNA, 33% a sustained loss of HBeAg, and 8% will lose
HBsAg over time. Liver function tests often flare during
treatment because the interferon triggers an immunologic
clearance of the virus. This event can cause acute hepatic
decompensation in patients with cirrhosis. Patients with
advanced cirrhosis should be treated with lamivudine.
Pegylated interferon is now being studied for the treatment of
chronic hepatitis B.
Cooksley and colleagues
looked at a 24-week course of pegylated interferon alfa-2a
compared with regular interferon alfa-2a. Twelve percent of
patients who received short-acting interferon, compared with
27% to 28% of patients who were treated with 90 or 180 mcg per
week of pegylated interferon, achieved a sustained response,
as defined by loss of HBeAg, undetectable HBV DNA by
hybridization assay, and ALT normalization. Pegylated
interferon may be one of the treatment approaches of the
future. Ribavirin, which is used in hepatitis C regimens, does
not have any activity against hepatitis B.
Lebensztejn and colleagues
looked at the sustained response to short-acting interferon
alfa given to 71 children with chronic hepatitis B. Thirty-two
of 71 (45%) developed a sustained response to 3 million units
of interferon alfa given 3 times per week for 20 weeks. The
patients were followed for 36 months and all of the responses
were durable. All patients had negative HBV DNA assays and
maintained their seroconversion to anti-HBe.
Nucleoside Analog Therapy
was approved by the FDA for the treatment of chronic hepatitis
B in 1999. The approved dose is 100 mg/day given orally for 1
year. Clinical trials
have shown response rates at 1 year that include a 32% loss of
HBeAg and a 17% seroconversion rate. Almost all patients
initially become HBV DNA-negative on treatment. Treatment
beyond 1 year is both controversial and problematic.
In one study of long-term therapy in Asian patients,
the HBeAg conversion rate was 47% after 4 years of continued
lamivudine treatment. Improvement in fibrosis occurs in
patients with cirrhosis and bridging fibrosis. Asians and
whites respond similarly to lamivudine therapy. Patients with
aminotransferases > 2x normal are candidates for treatment.
Patients with aminotransferases > 5x normal clear HBeAg in
50% to 60% of cases with 1 year of treatment, compared with
25% to 30% of patients with aminotransferases between 2x-5x
that of normal. This finding is similar to that observed with
interferon, in which case the response is better if the
patient has aminotransferases increased > 5x normal. The
incidence of lamivudine resistance increases proportionately
with the duration of treatment. YMDD-resistant mutations in
HBV DNA polymerase develop in 20%, 38%, 49%, and 66% after
1,2,3, and 4 years of continued treatment.[12,13]
YMDD resistance is generally associated with lower HBV DNA
levels and lower aminotransferase elevations compared with
before treatment. However, the long-term natural history of
YMDD-resistant mutants is unknown in patients who have been
treated with lamivudine. Although generally these mutants do
not cause a major reactivation of chronic hepatitis B,
fulminant hepatitis has been reported.
On the other hand, emergence of YMDD mutants can be associated
with continued control of the disease. I am currently treating
a patient with HBV-induced polyarteritis nodosa who presented
with abdominal pain, peripheral neuropathy, hypertension, and
significant renal failure. He has been on lamivudine for 20
months. Fourteen months into treatment, he developed YMDD-resistant
mutants, with a rise in his HBV DNA from nondetectable to
14,000,000 copies/mL. He has not developed a recurrence of his
disease. Presumably, the lamivudine is still suppressing the
wild-type hepatitis virus, which caused the vasculitis
initially (Geoffrey L. Braden, 2002; personal observation).
Adefovir dipivoxil is currently under review by the FDA for
treatment of wild-type and lamivudine-resistant chronic
hepatitis B. It has in vitro and in vivo activity against
wild-type and YMDD variants. The dose is 10 mg, given once
daily. It appears to be effective and no resistance has been
reported out to 136 weeks of treatment.[4,15,16]
Adefovir can cause renal insufficiency and is contraindicated
in patients with chronic renal failure. Entecavir is another
nucleoside analog under study for the treatment of chronic
hepatitis B. It is a potent inhibitor of HBV DNA polymerase
and is also active against wild-type virus and lamivudine-resistant
Lamivudine can be given to patients with decompensated
cirrhosis due to chronic hepatitis B. It has been reported to
increase albumin levels, decrease bilirubin levels, decrease
Child-Pugh scores, prolong survival, and possibly delay the
need for liver transplantation.
Future strategies may use adefovir and lamivudine in
combination to treat patients in this setting. Trials are
currently in progress using short-acting interferon or
pegylated interferon in combination with lamivudine. The
preliminary results of these studies appear promising. Other
nucleoside analogues under study for treatment of chronic
hepatitis B include famciclovir, emtricitabine, and tenofovir.
Lim and colleagues presented a phase 2 dose-ranging study of Val-LdC, an
L-nucleoside agent with activity against hepatitis B. Patients
were treated for 28 days and achieved a 3.6-log10
drop in HBV viral loads.
Treatment of HBeAg-Negative Chronic Hepatitis B
response to treatment in patients with precore/core promoter
mutations is not predicted by baseline ALT or HBV DNA levels.
HBV DNA levels are lower in these patients than in patients
with wild-type virus, and it may be necessary to use PCR
assays to follow the response to treatment. If interferon is
used, patients should be treated for at least 12 months. When
lamivudine is employed, there is a high rate of relapse in
patients who respond to 1 year of therapy. Treatment beyond 1
year may be necessary, but is of unproven value. The natural
history of YMDD mutants developing in patients with precore/core
promoter variants treated with lamivudine is unknown. Better
treatment for this subgroup is a subject of major clinical
effective therapy is needed for the treatment of patients with
chronic hepatitis B. Current therapies produce a complete cure
(loss of HBsAg) in only 8% to 10% of patients. The current
goals of treatment are to produce HBeAg seroconversion, which
usually results in a significant improvement in liver
histology and may slow or prevent the development of
cirrhosis. Currently, candidates for treatment include
patients with aminotransferases > 2x normal, chronic
hepatitis on liver biopsy, HBV DNA levels > 100,000 by
hybridization assay, and HBeAg positivity. The future is
bright for the development of new nucleoside analogs that will
be used alone or in combination with interferon or other
nucleoside agents, in a manner similar to that currently
employed to treat other chronic viral diseases, such as HIV.
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- Manno M, Grottola A, Ferretti I, et al. Natural
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- Perrillo R. Hepatitis B: Treatment, AASLD
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Francisco, California. [Sp419]
- Chu CJ, Keefe EB, Han SH, et al. HBV Genotypes in
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- Chien RN, Liaw YF, Tsai SL. HBV genotype is the
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- Watanabe H, Enomoto N, Ikeda T, et al.
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- Cooksley GE, Piratvisuth T, Wang YJ, et al. 40
KDA Peginterferon alpha 2a (Pegasys): Efficacy and safety
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- Chang TT, Lai CL, Liaw YF, et al. Incremental
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- Wang JH, Lu SN, Lee CM, et al. Fatal hepatic
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- Marcellin P, Chang TT, Lim SG, et al. Adefovir
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hepatitis B. Gastroenterology. 2002;122:P-216. [Poster
- Peters M, Schiff E, Benhamou Y, et al. Adefovir
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